Biology subjects

Rangel, A.

Publications and source records attributed to Rangel, A..

7 recordsLinked to original sources

bioRxiv2024

Modality-Specific and Amodal Language Processing by Single Neurons

According to psycholinguistic theories, during language processing, spoken and written words are first encoded along independent phonological and orthographic dimensions, then enter into modality-independent syntactic and semantic codes. Non-invasive brain imaging has isolated several cortical regions putatively associated with those processing stages, but lacks the resolution to identify the corresponding neural codes. Here, we describe the firing responses of over 1000 neurons, and mesoscale field potentials from over 1400 microwires and 1500 iEEG contacts in 21 awake neurosurgical patients with implanted electrodes during written and spoken sentence comprehension. Using forward modeling of temporal receptive fields, we determined which sensory or abstract dimensions are encoded. We observed a double dissociation between superior temporal neurons sensitive to phonemes and phonological features and previously unreported ventral occipito-temporal neurons sensitive to letters and orthographic features. We also discovered novel neurons, primarily located in middle temporal and inferior frontal areas, which are modality-independent and show responsiveness to higher linguistic features. Overall, these findings show how language processing can be linked to neural dynamics, across multiple brain regions at various resolutions and down to the level of single neurons.

neuroscience↗

bioRxiv2024

Novel tools to quantify total, phospho-Ser129 and aggregated alpha-synuclein in the mouse brain

Assays for quantifying aggregated and phosphorylated (S129) human -synuclein protein are widely used to evaluate pathological burden in patients suffering from synucleinopathy disorders. Many of these assays, however, do not cross-react with mouse -synuclein or exhibit poor sensitivity for this target, which is problematic considering the preponderance of mouse models at the forefront of pre-clinical -synuclein research. In this project, we addressed this unmet need by reformulating two existing AlphaLISA(R) SureFire(R) UltraTM total and pS129 -synuclein assay kits to yield robust and ultrasensitive (LLoQ [≤]0.5pg/mL) quantification of mouse and human wild-type and pS129 -synuclein protein. We then employed these assays, together with the BioLegend -synuclein aggregate ELISA, to assess the relationship between -synuclein S129 phosphorylation and aggregation in different mouse brain tissue preparations. Overall, we highlight the compatibility of these new immunoassays with rodent models and demonstrate their potential to advance knowledge surrounding -synuclein phosphorylation and aggregation in synucleinopathies.

neuroscience↗

bioRxiv2022

Automated patch clamp screening of amiloride and 5-N,N-hexamethyleneamiloride (HMA) analogs identifies 6-iodoamiloride as a potent acid-sensing ion channel inhibitor.

Acid-sensing ion channels (ASICs) are transmembrane sensors of extracellular acidosis and potential drug targets in several disease indications, including neuropathic pain and cancer metastasis. The K+-sparing diuretic amiloride is a moderate non-specific inhibitor of ASICs and has been widely used as a probe for elucidating ASIC function. In this work, we screened a library of 6-substituted and 5,6-disubstituted amiloride analogs using a custom-developed automated patch-clamp protocol and identified 6-iodoamiloride as a more potent ASIC1 inhibitor. Follow-up IC50 determinations in tsA-201 cells confirmed higher ASIC1 inhibitory potency for 6-iodoamiloride 97 (hASIC1 97 IC50 88 nM cf. amiloride 11 IC50 1.7 M). A similar improvement in activity was observed in ASIC3-mediated currents from rat small diameter dorsal root ganglion neurons (rDRG single-concentration 97 IC50 230 nM cf. 11 IC50 2.7 M). 6-iodoamiloride represents the amiloride analogue of choice for studying the effects of ASIC inhibition on cell physiology.

pharmacology and toxicology↗

bioRxiv2021

Straintables: An application that extracts sequences fromgenome assemblies and generates dissimilarity matrices

Background and ObjectivesThe dissimilarity matrix (DM) is an important component of phylogenetic analysis, and many software packages exist to build and show DMs. However, as the common input for this type of software are sequences in FASTA file format, the process of extracting and aligning each set of sequences to produce a big number of matrices can be laborious. Additionally, existing software do not facilitate the comparison of clusters of similarity across several DMs built for the same group of individuals, using different genomic regions. To address our requirements of such a tool, we designed Straintables to extract specific genomic region sequences from a group of intraspecies genomic assemblies, using extracted sequences to build dissimilarity matrices. MethodsA Python module with executable scripts was developed for a study on genetic diversity across strains of Toxoplasma gondii, being a general purpose system for DM calculation and visualization for preliminary phylogenetic studies. For automatic region sequence extraction from genomic assemblies we assembled a system that designs virtual primers using reference sequences located at genomic annotations, then matches those primers on genome files by using regex patterns. Extracted sequences are then aligned using Clustal Omega and compared to generate matrices. ResultsUsing this software saves the user from manual preparation and alignment of the sequences, a process that can be laborious when a large number of assemblies or regions are involved. The automatic sequence extraction process can be checked against BLAST results using extracted sequence as queries, where correct results were observed for same-species pools for various organisms. The package also contains a matrix visualization tool focused on cluster visualization, capable of drawing matrices into image files with custom settings, and features methods of reordering matrices to facilitate the comparison of clustering patterns across two or more matrices. ConclusionStraintables may replace and extend the functionality of existing matrix-oriented phylogenetic software, featuring automatic region extraction from genomic assemblies and enhanced matrix visualization capabilities emphasizing cluster identification. This module is open source, available at GitHub (https://github.com/Gab0/straintables) under a MIT license and also as a PIPY package. HighlightsSimple in-silico protocol for generation, visualization and comparison of dissimilarity matrices. Accurate automatic sequence extraction from multiple genomic assemblies by using virtual primers built from reference sequences in an annotation file. Draws matrices as images, with enhanced cluster visualization and customized options. Supports reordering of matrix indices to better visualize clustering pattern conservation across multiple regions.

bioinformatics↗

bioRxiv2020

Evidence accumulation, not "self-control,"explains why the dlPFC activates during normative choice

What role do cognitive control regions like the dorsolateral prefrontal cortex (dlPFC) play in normative behavior (e.g., generosity, healthy eating)? Some models suggest that dlPFC activation during normative choice reflects the use of control to overcome default hedonistic preferences. Here, we develop an alternative account, showing that an attribute-based neural drift diffusion model (anDDM) predicts trial-by-trial variation in dlPFC response across three fMRI studies and two self-control contexts (altruistic sacrifice and healthy eating). Using the anDDM to simulate a variety of self-control dilemmas generated a novel prediction: although dlPFC activity might typically increase for norm-consistent choices, deliberate self-regulation focused on normative goals should decrease or even reverse this pattern (i.e., greater dlPFC response for hedonic, self-interested choices). We confirmed these predictions in both altruistic and dietary choice contexts. Our results suggest that dlPFC response during normative choice may depend more on value-based evidence accumulation than inhibition of our baser instincts.

neuroscience↗

bioRxiv2020

Automated platform for high-throughput screening of base-modified aptamers for affinity and specificity

Aptamers incorporating chemically modified bases can achieve superior affinity and specificity compared to natural aptamers, but their characterization remains a labor-intensive, low-throughput task. Here we describe the non-natural aptamer array (N2A2) system, in which a minimally modified Illumina MiSeq instrument is used for the high-throughput generation and characterization of large libraries ([~]106) of base-modified DNA aptamer candidates on the basis of both target affinity and specificity. We first demonstrate the capability to screen multiple different base modifications to identify the optimal chemistry for high-affinity target binding. We next use N2A2 to generate aptamers that can maintain excellent specificity even in complex samples, with equally strong target affinity in both buffer and diluted human serum. Given that N2A2 requires only minor mechanical modifications to the MiSeq, we believe N2A2 offers a broadly accessible tool for generating high-quality affinity reagents for diverse applications.

bioengineering↗

bioRxiv2019

A response to Zhang et al. (2018), \"Can Mouse-tracking Reveal Attribute Processing Speeds in Dietary Self-control? Commentary on Sullivan et al. (2015) and Lim et al. (2018)\"

Introduction Introduction References In Sullivan et al. (2015), mouse-tracking was used in a food choice paradigm to test two related hypotheses: 1) that there are differences in the relative speed with which the decision-making circuitry computes and weights the value of attributes like health and taste; and, 2) that individual differences in these relative speeds are associated with individual differences in the ability to make healthy dietary choices. Consistent with these hypotheses, a regression analysis of the mouse-tracking paths found that health became significantly predictive of the mouses angle of movement ~195 ms later than taste, on average. Moreover, individual dietary self-control varied with estimates of the individual differences in the relative speed with which taste (tTaste) and health (tHealth) entered the decision-making process. Similar results have ...

neuroscience↗